Promoter-dependent Synergy between Glucocorticoid Receptor and Stat5 in the Activation of β-Casein Gene Transcription

Lechner, Judith; Welte, Thomas; Tomasi, J.; Bruno, P.; Cairns, Carol; Gustafsson, Jan Åke; Doppler, Wolfgang

doi:10.1074/jbc.272.33.20954

Cited by 118 publications

(83 citation statements)

References 51 publications

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“…Two half GRE sites were found, but there was an absence of a full GRE. Whereas these noncanonical half sites may impart GC regulation for some genes (19), we also examined the involvement of STAT5 and GR in transduction pathways for regulation of other GCcontrolled genes (20)(21)(22). Two STAT5-REs were identified in the mZnT2 promoter (23).…”

Section: Resultsmentioning

confidence: 99%

“…Of note, RU486 blocked the induction of both ZnT2 and MT genes by DEX, which is consistent with GR dimerization. Of relevance is that STAT5-GR interactions are responsible for regulation of the β-casein gene by glucocorticoids and prolactin in mammary cells (22). Because both are lactogenic hormones, it is most relevant that ZnT2 has also recently been shown to be regulated by prolactin through a JAK2/STAT5 mechanism in mammary cells (23).…”

Section: Discussionmentioning

confidence: 99%

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STAT5-glucocorticoid receptor interaction and MTF-1 regulate the expression of ZnT2 (Slc30a2) in pancreatic acinar cells

Guo

Lichten

Ryu

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

112

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The exocrine pancreas plays an important role in endogenous zinc loss by regulating excretion into the intestinal tract and hence influences the dietary zinc requirement. The present experiments show that the zinc transporter ZnT2 (Slc30a2) is localized to the zymogen granules and that dietary zinc restriction in mice decreased the zinc concentration of zymogen granules and ZnT2 expression. Excess zinc given orally increased ZnT2 expression and was associated with increased pancreatic zinc accumulation. Rat AR42J acinar cells when induced into a secretory phenotype, using the glucocorticoid analog dexamethasone (DEX), exhibited increased ZnT2 expression and labile zinc as measured with a fluorophore. DEX administrated to mice also induced ZnT2 expression that accompanied a reduction of the pancreatic zinc content. ZnT2 promoter analyses identified elements required for responsiveness to zinc and DEX. Zinc regulation was traced to a MRE located downstream from the ZnT2 transcription start site. Responsiveness to DEX is produced by two upstream STAT5 binding sites that require the glucocorticoid receptor for activation. ZnT2 knockdown in the AR42J cells using siRNA resulted in increased cytoplasmic zinc and decreased zymogen granule zinc that further demonstrated that ZnT2 may mediate the sequestration of zinc into zymogen granules. We conclude, based upon experiments with intact mice and pancreatic acinar cells in culture, that ZnT2 participates in zinc transport into pancreatic zymogen granules through a glucocorticoid pathway requiring glucocorticoid receptor and STAT5, and zinc-regulated signaling pathways requiring MTF-1. The ZnT2 transporter appears to function in a physiologically responsive manner involving entero-pancreatic zinc trafficking.M ammalian zinc homeostasis is maintained through a balance between gastrointestinal absorption, tissue turnover, and biliary, pancreatic, and intestinal secretions into the intestinal lumen (1). Under conditions of normal dietary zinc intake, substantial amounts of zinc are released into the small intestine from the exocrine pancreas (2, 3). These secretions represent a major component of calculations used to establish the dietary zinc requirement for humans.Over 85% of the pancreas is comprised of exocrine cells (4). Localization studies have shown that pancreatic zinc is concentrated in the granules of acinar cells, where digestive proenzymes are also stored prior to exocytosis through the apical membrane for entry into the intestinal lumen. Abnormal zinc metabolism has been reported after pancreatectomy (5-7). Zinc deficiency causes pancreatic acinar cells to become depleted of zinc (8,9). Radiotracer studies have shown that the pancreas exhibits high rates of zinc turnover [reviewed in (10)]. The exocrine pancreas is a target organ of zinc toxicosis. Excessive dietary zinc alters acinar cell structure, and produces necrosis, causing depletion of zymogen granules and reduces digestive enzyme secretion (11-13). This sensitivity to zinc supports the need for tight re...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

STAT5-glucocorticoid receptor interaction and MTF-1 regulate the expression of ZnT2 (Slc30a2) in pancreatic acinar cells

Guo

Lichten

Ryu

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

112

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“…The mouse ␤-casein promoter contains binding sites for STAT5 and C/EBP␤, and half-sites of the palindromic glucocorticoid response element (33)(34)(35). To determine whether ECM and prolactin directly induce transcriptional activation of the ␤-casein promoter, we amplified and cloned the promoter region from Ϫ340 to Ϫ1 into a luciferase reporter vector and stably transfected the reporter plasmid into EpH4 cells.…”

Section: Resultsmentioning

confidence: 99%

Extracellular Matrix-regulated Gene Expression Requires Cooperation of SWI/SNF and Transcription Factors

Spencer

Bissell

2007

Journal of Biological Chemistry

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Extracellular cues play crucial roles in the transcriptional regulation of tissue-specific genes, but whether and how these signals lead to chromatin remodeling is not understood and subject to debate. Using chromatin immunoprecipitation assays and mammary-specific genes as models, we show here that extracellular matrix molecules and prolactin cooperate to induce histone acetylation and binding of transcription factors and the SWI/SNF complex to the ␤-and ␥-casein promoters. Introduction of a dominant negative Brg1, an ATPase subunit of SWI/ SNF complex, significantly reduced both ␤-and ␥-casein expression, suggesting that SWI/SNF-dependent chromatin remodeling is required for transcription of mammary-specific genes. Chromatin immunoprecipitation analyses demonstrated that the ATPase activity of SWI/SNF is necessary for recruitment of RNA transcriptional machinery, but not for binding of transcription factors or for histone acetylation. Co-immunoprecipitation analyses showed that the SWI/SNF complex is associated with STAT5, CCAAT/enhancer-binding protein ␤, and glucocorticoid receptor. Thus, extracellular matrix-and prolactin-regulated transcription of the mammary-specific casein genes requires the concerted action of chromatin remodeling enzymes and transcription factors.Differentiated function of mammary epithelial cells is regulated by signals from both ECM 2 and lactogenic hormones (1-3). The gene encoding the milk protein, ␤-casein, has been used widely as a marker for functional differentiation of MECs. We and others have shown that in both primary mouse mammary epithelial cells and immortalized mammary epithelial cell lines (4 -6), transcription of ␤-casein requires signals from both laminin-111 (previously referred to as laminin-1) and prolactin (1, 2, 7-10). A number of transcription factors, including STAT5, C/EBP␤, and GR, have been shown to be involved in this process (reviewed in Ref. 7).Modulation of chromatin structure by histone modifications and ATP-dependent remodeling has been implicated in cell differentiation and transcriptional control of tissue-specific and inducible genes (11-13). Histone-modifying enzymes are believed to be recruited to promoter regions through their association with transcription factors and are critical for tissue-specific gene expression and functional differentiation of specific cell types (14, 15). Histone acetylation is a dynamic process and is regulated by histone acetyltransferases and histone deacetylases (16). The mapping of global histone acetylation patterns has demonstrated that chromatin accessibility and gene expression are correlated with histone hyperacetylation of promoters and other cis-elements (17, 18). The p300 histone acetyltransferase cooperates with STAT5 to enhance exogenous ␤-casein promoter activity in COS cells, indicating that histone acetylation may play a role in ␤-casein transcription (19). Trichostatin A (TSA), an inhibitor of histone deacetylase, was shown to activate the bovine casein ECM response element (BCE-1) in an ECM-independent...

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“…It has been demonstrated that dexamethasone (DEX), a synthetic glucocorticoid, reverses PRL-induced upregulation of islet function by inhibiting glucose metabolism (Shao et al 2004), PDX-1 expression (Nasir et al 2005), insulin secretion, and cell proliferation, and by increasing apoptosis (Weinhaus et al 2000). Curiously, GCs have been reported to strongly synergize with PRL-induced STAT5 activation through distinct mechanisms involving the glucocorticoid receptor (Stocklin et al 1996, Lechner et al 1997, Wyszomierski et al 1999. Therefore, a distinct mechanism activated by PRL, other than the activation of the JAK2/STAT5 pathway, is likely to be negatively modulated by GCs in pancreatic b-cells.…”

Section: Introductionmentioning

confidence: 99%

Signal transducer and activator of transcription 3-regulated sarcoendoplasmic reticulum Ca2+-ATPase 2 expression by prolactin and glucocorticoids is involved in the adaptation of insulin secretory response during the peripartum period

Anhê

Nogueira

Nicoletti-Carvalho

et al. 2007

Journal of Endocrinology

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During pregnancy, the maternal endocrine pancreas undergoes, as a consequence of placental lactogens and prolactin (PRL) action, functional changes that are characterized by increased glucose-induced insulin secretion. After delivery, the maternal endocrine pancreas rapidly returns to nonpregnant state, which is mainly attributed to the increased serum levels of glucocorticoids (GCs). Although GCs are known to decrease insulin secretion and counteract PRL action, the mechanisms for these effects are poorly understood. We have previously demonstrated that signal transducer and activator of transcription 3 (STAT3) is increased in islets treated with PRL. In the present study, we show that STAT3 expression and serine phosphorylation are increased in pancreatic islets at the end of pregnancy (P19). STAT3 serine phosphorylation rapidly returned to basal levels 3 days after delivery (L3). The expression of the sarcoendoplasmic reticulum Ca 2C -ATPase 2 (SERCA2), a crucial protein involved in the regulation of calcium handling in b-cells, was also increased in P19, returning to basal levels at L3. PRL increased SERCA2 and STAT3 expressions and STAT3 serine phosphorylation in RINm5F cells. The upregulation of SERCA2 by PRL was abolished after STAT3 knockdown. Moreover, PRL-induced STAT3 serine phosphorylation and SERCA2 expression were inhibited by dexamethasone (DEX). Insulin secretion from islets of P19 rats pre-incubated with thapsigargin and L3 rats showed a dramatic suppression of first phase of insulin release. The present results indicate that PRL regulates SERCA2 expression by a STAT3-dependent mechanism. PRL effect is counteracted by DEX and might contribute to the adaptation of maternal endocrine pancreas during the peripartum period.

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Promoter-dependent Synergy between Glucocorticoid Receptor and Stat5 in the Activation of β-Casein Gene Transcription

Cited by 118 publications

References 51 publications

STAT5-glucocorticoid receptor interaction and MTF-1 regulate the expression of ZnT2 (Slc30a2) in pancreatic acinar cells

STAT5-glucocorticoid receptor interaction and MTF-1 regulate the expression of ZnT2 (Slc30a2) in pancreatic acinar cells

Extracellular Matrix-regulated Gene Expression Requires Cooperation of SWI/SNF and Transcription Factors

Signal transducer and activator of transcription 3-regulated sarcoendoplasmic reticulum Ca2+-ATPase 2 expression by prolactin and glucocorticoids is involved in the adaptation of insulin secretory response during the peripartum period

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